1. Field of the Invention
This invention relates to a new use of the phenothiazine drugs and more particularly to their use as protozoacides against members of the protozoan family Trypanosomatidae.
2. Description of the Prior Art
The Trypanosoma and Leishmania are the only genera of the family Trypanosomatidae that are pathogenic for humans or animals. The first genus, Trypanosoma, causes a group of closely related disease of man and animals known as trypanosomiasis. Two general forms of the disease are recognized: African trypanosomiasis, occurring mainly but not exclusively in tropical Africa, and American trypanosomiasis or Chagas' disease, which occurs mainly in Central and South America. Various forms of the disease caused by different species of protozoa include sleeping sickness (humans and cattle), nagana (domestic animals), secadera (domestic animals), surra disease (domestic animals), mal de caderas (horses), and Chagas' disease (humans). The second pathogenic genus, Leishmania, consists of intracellular parasites that cause a complex of diseases known as leishmaniasis. Two forms of the disease are recognized: visceral leishmaniasis caused by L. donovani and known as kala-azar (black fever), and mucocutaneous and cutaneous leishmaniasis, caused by L. tropica, L. mexicana, and L. braziliensis and known by various names, including oriental sore, espundia, and Bay sore. Leishmania change in form when transmitted from insects to mammals. The amastigote stage is found within white cells in the mammalian host. The promastigote stage of the organism is found only in the insect host. When a sandfly bites a susceptible host, promastigotes are inoculated, convert to amastigotes, and go on to produce disease. When the sandfly bites a mammal with leishmaniasis, it acquires amastigotes which convert to promastigotes in its gut.
There is now no uniformly effective, non-toxic form of therapy for any of the major tropical diseases of humans or domestic animals caused by these parasites. Chemotherapy has been tried but with only limited success. Suramin, ##STR1## is active against some trypanosome infections but is not active against T. cruzi. In addition, an unacceptable incidence of local severe reactions in patients after intramuscular injection precludes wide spread usage for humans. Arsenicals and antimonials have found use against both leishmaniasis and trypanosomiasis, but have obvious limitations because of their general toxicity. Nevertheless, tryparsamide is still widely used in the treatment of West African sleeping sickness and sodium stibogluconate has remained one of the drugs of choice available in the treatment of leishmaniasis. ##STR2## The chemotherapy of both trypanosomiasis and leishmaniasis is reviewed in W. J. Ross, "Chemotherapy of Trypanosomiasis and other Protozoan Diseases", Burger's Medicinal Chemistry, 4th Ed., Part II, pp. 439-479, M. E. Wolff, ed., John Wiley & Sons, New York (1979).
Because of the deleterious side effects of known chemotherapeutic agents, a continuing need for new protozoacides against Trypanosomatidae exists. In addition, because the diseases caused by these protozoa occur principally in the underdeveloped nations of the world, a drug that can be administered orally by unskilled workers and which has known, minimal side effects is highly desirable.